Journal
BLOOD
Volume 140, Issue 11, Pages 1278-1290Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2021015019
Keywords
-
Categories
Funding
- National Institutes of Health (NIH)
- National Cancer Institute (NCI) [UH2 CA206127-02, P01 CA229100]
- Leukemia and Lymphoma Society [TRP-6129-04]
- NIH NCI Eppley Cancer Center [P30 CA036727]
- NIH NCI Strategic Partnering to Evaluate Cancer Signatures (SPECS) II [5 UO1 CA157581-01]
- City of Hope internal funds
- AIRC 5x1000 grant [21198]
- University of Nebraska Medical Center NIH [5T32CA009476-23]
- National Institute for General Medical Science (NIGMS) IDeA Net-works of Biomedical Research Excellence [P20GM103427-14]
- Centers of Biomedical Research Excellence [1P30GM110768-01]
- NIH NCI Specialized Programs of Research Excellence
- Fred & Pamela Buffett Cancer Center Support Grant [P30CA036727]
- [1P50 CA136411-01 01A1 PP-4]
Ask authors/readers for more resources
This study investigated the role of DNMT3A mutations in PTCL and found that DNMT3A mutations, particularly in PTCL-TBX21 cases, are associated with inferior overall survival and enrichment of activated CD8+ T-cell cytotoxic gene signatures. Genomewide methylation analysis demonstrated hypomethylation of target genes regulating interferon-gamma, T-cell receptor signaling, and EOMES in DNMT3A-mutant PTCL-TBX21 cases. Functional experiments using mouse models and in vitro cell cultures confirmed the impact of DNMT3A mutations on T-cell activation and cytotoxic effector cell transcriptional regulation.
Peripheral T-cell lymphomas (PTCLs) are heterogenous T-cell neoplasms often associated with epigenetic dysregulation. We investigated de novo DNA methyltransferase 3A (DNMT3A) mutations in common PTCL entities, including angioimmunoblastic T-cell lymphoma and novel molecular subtypes identified within PTCL-not otherwise specified (PTCL-NOS) designated as PTCL-GATA3 and PTCL-TBX21. DNMT3A-mutated PTCL-TBX21 cases showed inferior overall survival (OS), with DNMT3A-mutated residues skewed toward the methyltransferase domain and dimerization motif (S881-R887). Transcriptional profiling demonstrated significant enrichment of activated CD8+ T-cell cytotoxic gene signatures in the DNMT3A-mutant PTCL-TBX21 cases, which was further validated using immunohistochemistry. Genomewide methylation analysis of DNMT3A-mutant vs wildtype (WT) PTCL-TBX21 cases demonstrated hypomethylation in target genes regulating interferon-gamma (IFN-gamma), T-cell receptor signaling, and EOMES (eomesodermin), a master transcriptional regulator of cytotoxic effector cells. Similar findings were observed in a murine model of PTCL with Dnmt3a loss (in vivo) and further validated in vitro by ectopic expression of DNMT3A mutants (DNMT3A-R882, -Q886, and -V716, vs WT) in CD8+ T-cell line, resulting in T-cell activation and EOMES upregulation. Furthermore, stable, ectopic expression of the DNMT3A mutants in primary CD3+ T-cell cultures resulted in the preferential outgrowth of CD8+ T cells with DNMT3AR882H mutation. Single-cell RNA sequencing(RNA-seq) analysis of CD3+ T cells revealed differential CD8+ T-cell subset polarization, mirroring findings in DNMT3A-mutated PTCL-TBX21 and validating the cytotoxic and T-cell memory transcriptional programs associated with the DNMT3AR882H mutation. Our findings indicate that DNMT3A mutations define a cytotoxic subset in PTCL-TBX21 with prognostic significance and thus may further refine pathological heterogeneity in PTCL-NOS and suggest alternative treatment strategies for this subset.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available